ABSTRACT Viral infections have more severe consequences in patients exposed to cigarette smoke (CS) than in non/never-exposed individuals. This is seen in smokers with COPD. It is also seen in otherwise healthy, influenza-infected smokers and respiratory syncytial virus-infected children exposed to second hand smoke. We compared the innate immune responses in mice exposed to room air (RA) or CS. CS enhanced the inflammatory, apoptotic and remodeling responses that were induced by Poly(I:C) (a viral innate immunity agonist or PAMP) and influenza virus. These responses were: (a) mediated by the RIG-like helicase (RLH) antiviral pathway, (b) mediated by an effector cascade that is downstream of RLH and includes type I and II Interferons, IL-18, double-Stranded RNA-Dependent Protein Kinase (PKR) and eukaryotic initiation factor- 2 (eIF2) and (c) associated with activation of the 2',5'-oligoadenylate synthase (OAS)/endoribonuclease L (RNaseL) antiviral pathway. Importantly, mice that had been exposed to CS manifest a Sca1+ epithelial cell repair response that was blunted by treatment with viruses/viral PAMPs. This led to the following multipart hypothesis. Hypothesis 1. CS augments RLH-mediated innate responses against viruses/viral PAMPs in the lung. 2. This exaggerated response is centered in the respiratory epithelium and plays a major role in the inflammation and remodeling caused by CS plus viruses/viral PAMPs. 3. The exaggerated alveolar remodeling that in mice exposed to CS and viruses/viral PAMPS is the result of the ability of RLH innate immune activation to activate both the PKR/eIF2 and the 2',5'OAS/RNase L antiviral systems to simultaneously induce epithelial injury and inhibit progenitor cell-based repair responses. Specific Aims. To test this hypothesis we propose to: 1. Define the helicases that mediate the effects of viruses/viral PAMPs in CS-exposed mice. 2. Define the role(s) of epithelial and macrophage RLH-mediated innate responses in the pathogenesis of the effects of CS plus viruses/viral PAMPs. 3. Define the mechanism by which RLH activation regulates epithelial cell injury/apoptosis in mice exposed to CS plus virus/viral PAMPs. 4. Define the mechanism by which RLH-mediated innate activation regulates progenitor cell based repair responses in mice exposed to CS plus virus/viral PAMPs.